Breast cancer is the most common malignancy among women worldwide. Breast cancers are classified into different categories based on their molecular and histopathological features. While disease severity can be stratified, a profound problem is the lack of effectiveness of many of the current treatment regimens. One of the greatest challenges in breast cancer management is recurrent disease, which affects 30 percent of breast cancer patients and is usually incurable. Part of the problem is that certain tumor cells remain undetected in the body for extended periods of time before they suddenly erupt into overt, life-threatening cancers. Patients with some types of breast cancers experience recurrence within months of their original diagnosis, while other patients relapse as late as 15-20 years after treatment. It is difficult to predict whether tumor cells that have spread throughou a patient's body will remain inactive or whether they will begin to grow and, if so, what triggers their growth. We propose to address these clinical problems by using our novel experimental mouse model system that gave us important insights into breast cancer pathophysiology. We learned that some tumors that would otherwise remain dormant can respond to certain growth factors and bone marrow-derived cells that circulate throughout the body, which we collectively refer to as the systemic environment. However, tumors are not just passive recipients of circulating growth factors and cells. Instead, certain tumors actively create a systemic environment that is favorable to the growth of disseminated tumor cells that otherwise would not grow in the normal, unperturbed systemic environment. We contend that many aspects of breast cancer biology can only be explained by a detailed understanding of both activation and response to the systemic environment. We propose to build upon our fundamental observations with the following specific aims: 1. Determine which types of breast cancers are capable of establishing a tumor-supportive systemic environment and how they do so. 2. Define the properties of breast cancers that are capable of responding to a tumor-promoting systemic environment. 3. Determine whether inhibiting certain aspects of the tumor-promoting environment will prevent the growth of otherwise indolent tumors. Understanding how certain tumors activate the systemic environment should help us to design therapies to inhibit their pro-tumorigenic functions. As importantly, understanding the properties of tumor cells that respond to these systemic factors should allow us to determine whether a patient harbors these responsive cells. These mechanistic studies have the potential to pave the way for more effective breast cancer therapies. PUBLIC HEALTH RELEVANCE: We propose to elucidate the pathophysiology of breast cancer relapse by building on our observations that have yielded fundamental insights into tumor progression. These observations suggest that cancer is a disease that is capable of creating and responding to a pro-tumorigenic host systemic environment. The knowledge we obtain from our proposed experiments should provide entry points for preclinical development of specific breast cancer therapies.